Chronic insomnia is a disorder afflicting as many as 10 percent of adults in the US, a substantial proportion of whom have no identifiable underlying cause for the sleep complaint, i.e. primary insomnia (PI). Several lines of evidence implicate central sympathetic nervous system (SNS) dysregulation in the pathogenesis of PI. First, patients with this disorder show evidence of SNS arousal, including increased basal metabolic rates, elevated circulating catecholamines, and increased daytime alertness relative to the degree of nocturnal sleep disruption. Along with the SNS, the hypothalamic pituitary adrenal (HPA) axis is also hyperactive in insomnia, implicating a central mechanism common to both axes. Second, epidemiological studies establish a strong link between patients with PI and patients with major depressive disorder (MDD), also characterized by central activation of the SNS and HPA axes. Third, corticotropic releasing factor (CRF), a link between the SNS and HPA axes implicated in the pathogenesis of MDD, causes sleep disruption and hyper-arousal when centrally administered in animal models. In this proposal, we present a model of primary insomnia in which the pathogenic mechanism of this disorder is hypothesized to be dysregulation of central CRF neurons, specifically the delayed restoration of normal CRF levels following stress. This model provides a conceptual foundation for 1) the temporal (intermittent) pattern of manifest sleep disruption in patients with underlying tendency to P1; 2) the link between insomnia and stress; 3) the epidemiological link between MDD and P1; and 4) the hyper-arousal in PI with activation of SNS and HPA axes. It also provides a focus for future therapeutic efforts for this important disorder, suggesting that antagonists of CRF may be useful in reversing insomnia, and in blocking the processes that eventuate in MDD. We propose three experiments to test the CRF model and some of its predictions. In the first experiment, we will examine the status of the SNS and HPA axes in patients with P1, and the clinical correlates of SNS-HPA activation in this population. Second, we will assess the role of the CRF-SNS response in perpetuating insomnia by comparing the effects of sleep disruption (audio tones) in patients with P1 and normal controls, using sleep continuity, urinary catecholamines, daytime function, and subsequent sleep as dependent measures. Finally, we will use a new measure of central CRF function, the DEX-sleep latency test, to test the hypothesis that central CRF tone is higher in patients with P1.